Published in:
European Journal of Biochemistry, 251 (1998) 1-2, Seite 208-216
Language:
English
DOI:
10.1046/j.1432-1327.1998.2510208.x
ISSN:
1432-1033;
0014-2956
Origination:
Footnote:
Description:
<jats:p>The formation of amyloid within the islets of Langerhans is associated with the development of type II diabetes mellitus and occurs by the aggregation and insolubilization of islet amyloid polypeptide (IAPP). Recent <jats:italic>in vitro</jats:italic> studies suggest that amyloid formation follows a nucleation‐dependent polymerization mechanism, i.e. aggregation is initiated by pre‐formed aggregates or nucleation seeds. Modification of the Alzheimer's disease amyloid peptide by advanced glycosylation end products (AGEs), which form spontaneously by the non‐enzymatic addition of glucose to protein amino groups, has been shown to enhance peptide aggregation <jats:italic>in vitro</jats:italic>. To explore the possibility that AGEs contribute to islet amyloid formation, we preparedAGE‐modified IAPP (AGE‐IAPP) <jats:italic>in vitro</jats:italic> and studied its properties by biochemical and biophysical techniques. AGE modification induced the formation of high‐molecular‐mass IAPP aggregates and amyloid formation was demonstrated by Congo red green‐gold birefringence and by the presence of a characteristic fibrillar structure by electron microscopy. AGE‐IAPP also showed an increase in cytotoxicity toward the astroglioma cell line HTB14. When added to soluble IAPP, AGE‐IAPP seeds accelerated IAPP aggregation and abolished the nucleation period required for the polymerization of unseeded IAPP. Circular dichroism spectropolarimetry indicated that AGE‐IAPP seeds may act as a template to stabilize the β‐sheet conformation of IAPP, thereby promoting its aggregation. Our studies demonstrate that AGE modification of IAPP results in high‐molecular mass, fibrillar amyloid structures that nucleate IAPP amyloid formation and suggest a model for intra‐islet amyloid deposition that may occur by the progressive advanced glycosylation of IAPP<jats:italic> in vivo</jats:italic>.</jats:p>